Explanation Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by mutations in the TSC1 or TSC2 gene, leading to development of hamartomas in the brain, kidneys, heart, lungs, eyes, and skin, A diagnostic evaluation for TSC includes: 1) family history, 2) skin, dental, and eye examination, 3) functional and imaging studies of internal organs depending on patient age and presentation, and 4) consideration of genetic testing. The decision to pursue a complete evaluation for TSC is readily made for those presenting early in life with multiple complications of their disease. This decision may be more difficult in those who manifest only one skin finding of TSC. In such instances, additional considerations enter the decision-making process, such as concern for causing unnecessary anxiety in the patient or family, possible health risks and financial costs to screen individuals with a seemingly low diagnostic yield, or the potential for misidentification or misattribution of skin lesions that pose little or no problem to the patient. For this reason, we developed a diagnostic and management algorithm for these individuals. Our goal was to identify situations that should increase suspicion for TSC and others where extensive TSC-related work-up may not be warranted. We evaluated the earliest cutaneous manifestations in a cohort of 124 adults with TSC. Based on these patients and our experience evaluating 13 additional patients screened for TSC, we proposed a new algorithm that refines the evaluation of those presenting with one skin finding suggestive for TSC. A retrospective review of medical records from patients recruited for studies of TSC and lymphangioleiomyomatosis (LAM) at the National Institutes of Health Clinical Center from 1998 to 2015 was performed. This cohort was enriched for patients diagnosed with TSC in adulthood, frequently after complications from renal angiomyolipomas or pulmonary LAM. Diagnosis based on clinical criteria; patients met updated criteria that outlines a definite diagnosis of TSC as two or more major features or one major feature plus two or more minor features. Individuals with only one major feature, or two or more minor features, were considered as having possible TSC. Skin findings that satisfy major features are hypomelanotic macules, angiofibromas or fibrous cephalic plaque, shagreen patch, and ungual fibromas. Our data reinforced the current consensus recommendation that all individuals manifesting one or more major features of TSC should undergo complete diagnostic evaluation. Additionally, the results obtained in patients referred for TSC screening suggest that an additional step, involving further characterization of the skin finding may help exclude TSC or lead to the identification of other diseases. In some instances, imaging and genetic testing may be helpful. We recommend use of this algorithm to guide the evaluation of patients at the first cutaneous sign of TSC so that treatment, preventative measures, disease counseling and/or plan for lifetime follow-up may be swiftly enacted. In TSC, cutaneous hamartoma formation occurs secondary to loss of function of either the TSC1 or TSC2 gene in fibroblast-like cells and subsequent dysregulation of the mechanistic target of rapamycin complex 1, or mTORC1. Angiofibromas are among the most well recognized TSC-related skin hamartomas and consist of multiple pink papules on the central face. We describe a previously unreported manifestation of TSC, angiofibromas of the nipple-areolar complex. Between October 2012 and January 2015, 53 TSC patients (50 women, 3 men) participated in studies of LAM, a TSC-associated lung disease with female predominance. Eleven TSC patients (10 women, 1 man; median age 41 years range 21-71 years) with papules on the nipple and/or areola were identified, eight of whom had germline mutations in TSC2. Clinical examination revealed 1 to 25, 1-3 millimeter, pink to red dome-shaped papules on the nipple and/or areola, affecting one or both breasts. Per patient recollection, the median age of onset was 33 years (n=7 women; range 16-38 years). One patient reported painless bleeding from her nipple papules during breastfeeding while the rest remained asymptomatic. Histopathological examination of ten biopsied nipple or areolar papules from seven patients revealed increased number of dilated capillaries in the papillary dermis and increased number of stellate and spindle-shaped fibroblasts interspersed in the dermal collagen, consistent with the diagnosis of an angiofibroma. Increased numbers of factor XIIIa positive spindle to stellate shaped cells were observed in the dermis of the nipple-areolar complex papules, as characteristically observed in TSC-related facial angiofibromas. In summary, we report a novel clinical manifestation of TSC, nipple-areolar complex angiofibromas. Similar to facial angiofibromas, they occur following second hit loss of the wild type allele of TSC2, but manifest much later in life. They have a benign clinical course, with symptomatic manifestations only associated with local trauma. When verified by histologic analysis, they may provide additional information in favor of TSC diagnosis. Oral mechanistic target of rapamycin (mTOR) inhibitors have been shown to reduce visceral tumor volume in TSC patients. Our objective in the current study was to evaluate the cutaneous response to oral sirolimus in TSC patients with an indication for systemic treatment, e.g., pulmonary LAM, including long-term effects. This retrospective analysis involved fourteen adult TSC patients prescribed sirolimus to treat LAM. Serial photographs of skin lesions such as angiofibromas, shagreen patches and ungual fibromas taken before, during and after the treatment period were blinded, then assessed using the Physicians Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. The results showed that sirolimus significantly improved angiofibromas (median treatment duration: 12 months; median PGA: 4.5 range 1.5-5; Wilcoxon signed-rank test, p= 0.018) and shagreen patches (10; 4.5 3.5-5; p=0.039), whereas ungual fibromas only improved in some patients (6.5; 4.66 2.75-5; p=0.109). Clinical, immunohistochemical or molecular evidence of resistance was not observed (range 5 to 64 months of treatment). The primary limitation of the study was that it involved a retrospective analysis limited to adult women with LAM. Based on these data , we conclude that oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.